Phase 1 trial of a novel antibody-targeted radiotherapy in patients with metastatic castrate-resistant prostate cancer (mCRPC)

This is a 3-part, multicentre, open-label Phase 1 study of ATNM-400, a HER3-targeted radiotherapy, in men with metastatic castrate-resistant prostate cancer (mCRPC). Part A – Imaging Lead-in ([89Zr]-barecetamab-DFO): Up to 10 participants will receive a single intravenous (IV) dose of [89Zr]-barecetamab-DFO at approximately 37 MBq (1 mCi) for imaging-only purposes. This radiolabelled antibody is a non-therapeutic surrogate of ATNM-400 and is used to assess tumor targeting, biodistribution, dosimetry, and pharmacokinetics. PET/CT imaging will be performed at multiple time points (2–336 hours post-dose) to determine organ and tumor uptake and confirm radiation safety for subsequent therapeutic dosing. All imaging doses will be prepared and administered by qualified nuclear medicine personnel (radiopharmacists, radiologists, or technologists) at participating sites in compliance with radiation safety regulations Part B – ATNM-400 Dose Escalation: Eligible participants will receive ATNM-400 ([225Ac]-barecetamab-DOTA) as an intravenous infusion on Day 1 of each 42-day treatment cycle, for up to four cycles. Dose escalation will follow a traditional 3+3 design across five planned cohorts, with dose levels ranging from 1.0 µCi/kg (0.037 MBq/kg) to 3.0 µCi/kg (0.11 MBq/kg). The infusion will be administered over approximately 30 minutes. Dose-limiting toxicities (DLTs) will be evaluated by the Safety Review Committee (SRC) to determine the maximum tolerated dose. Participants from Part A who demonstrate tumour uptake and meet eligibility criteria may re-enroll into Part B. Part C – ATNM-400 Dose Expansion: Approximately 18 participants will receive ATNM-400 at the maximum tolerated dose (MTD) determined in Part B. Part C will begin after the final participant in Part B has completed the DLT observation period and the SRC has confirmed the MTD, which is typically within two to four weeks after the last Part B participant’s DLT window. Participants from Part B will not be re-treated in Part C; only newly enrolled participants will receive expansion dosing. ATNM-400 will be administered as an intravenous infusion on Day 1 of each 42-day treatment cycle for up to four cycles. Each cycle may be extended to 56 days if additional time is required for hematologic recovery, although dosing will continue to occur once per cycle regardless of cycle length.